U.S. patent application number 17/441234 was filed with the patent office on 2022-06-02 for therapeutic agent for parkinson's disease.
This patent application is currently assigned to KYOWA KIRIN CO., LTD.. The applicant listed for this patent is KYOWA KIRIN CO., LTD.. Invention is credited to Nobutaka HATTORI, Tomoyuki KANDA, Hiroki KITABAYASHI, Akihisa MORI, Takanobu NOMURA.
Application Number | 20220168311 17/441234 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-02 |
United States Patent
Application |
20220168311 |
Kind Code |
A1 |
KANDA; Tomoyuki ; et
al. |
June 2, 2022 |
THERAPEUTIC AGENT FOR PARKINSON'S DISEASE
Abstract
A therapeutic agent for Parkinson's disease containing
istradefylline as an effective ingredient being characterized in
exhibiting more expression of a shortening effect of the OFF time
by administration to a patient of Parkinson's disease of 65 or more
years old as compared with administration to a patient of
Parkinson's disease of younger than 65 years old.
Inventors: |
KANDA; Tomoyuki; (Tokyo,
JP) ; MORI; Akihisa; (Tokyo, JP) ;
KITABAYASHI; Hiroki; (Tokyo, JP) ; NOMURA;
Takanobu; (Tokyo, JP) ; HATTORI; Nobutaka;
(Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KYOWA KIRIN CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
KYOWA KIRIN CO., LTD.
Tokyo
JP
|
Appl. No.: |
17/441234 |
Filed: |
March 19, 2020 |
PCT Filed: |
March 19, 2020 |
PCT NO: |
PCT/JP2020/012509 |
371 Date: |
September 20, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62821961 |
Mar 21, 2019 |
|
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International
Class: |
A61K 31/522 20060101
A61K031/522; A61K 31/198 20060101 A61K031/198; A61P 25/16 20060101
A61P025/16 |
Claims
1-18. (canceled)
19. A method for more expressing an effect of shortening an OFF
time in treatment of Parkinson's disease as compared with the case
where a therapeutic agent for Parkinson's disease containing
istradefylline as an active ingredient is administered to a patient
of Parkinson's disease of younger than 65 years old, comprising
administering the therapeutic agent for Parkinson's disease
containing istradefylline as an active ingredient to a patient of
Parkinson's disease of 65 or more years old.
20. The method according to claim 19, wherein the more expressing
the effect of shortening the OFF time is that a rate of a patient
where the OFF time is shortened for long time is high.
21. The method according to claim 19, wherein the effect of
shortening the OFF time is that the OFF time is shortened for 1
hour or longer as compared with the case where a placebo is
administered, and the more expressing the effect of shortening the
OFF time is that the effect of shortening the OFF time is
significantly improved in terms of odds ratio when the agent is
administered to a patient of Parkinson's disease of 65 or more
years old, as compared to the case where the agent is administered
to a patient of Parkinson's disease of younger than 65 years
old.
22. A method for more expressing an effect of increasing an ON time
without troublesome dyskinesia in treatment of Parkinson's disease
as compared with the case where a therapeutic agent for Parkinson's
disease containing istradefylline as an active ingredient is
administered to a patient of Parkinson's disease of younger than 65
years old, comprising administering the therapeutic agent for
Parkinson's disease containing istradefylline as an active
ingredient to a patient of Parkinson's disease of 65 or more years
old.
23. The method according to claim 22, wherein the more expressing
the effect of increasing the ON time without troublesome dyskinesia
in the treatment of Parkinson's disease is that a rate of a patient
where the ON time without troublesome dyskinesia is extended for
long time is high.
24. The method according to claim 22, wherein the effect of
increasing the ON time without troublesome dyskinesia is that the
ON time without troublesome dyskinesia is extended for one hour or
more as compared with the case when a placebo is administered, and
the more expressing the effect of increasing the ON time without
troublesome dyskinesia is that the effect of increasing the ON time
without troublesome dyskinesia is significantly improved in terms
of odds ratio when the agent is administered to a patient of
Parkinson's disease of 65 or more years old, as compared to the
case where the agent is administered to a patient of Parkinson's
disease of younger than 65 years old.
25. A method for more expressing an effect of improving the UPDRS
Part III score as compared with the case where a therapeutic agent
for Parkinson's disease containing istradefylline as an active
ingredient is administered to a patient of Parkinson's disease
where a UPDRS Part III score is less than 20 points before the
treatment with the therapeutic agent for Parkinson's disease,
comprising administering the therapeutic agent for Parkinson's
disease containing istradefylline as an active ingredient to a
patient of Parkinson's disease where a UPDRS Part III score is 20
points or more before the treatment with the therapeutic agent for
Parkinson's disease.
26. The method according to claim 25, wherein the more expressing
the effect of improving the UPDRS Part III score is that a rate of
a patient where the UPDRS Part III score is improved is high.
27. The method according to claim 25, wherein the effect of
improving the UPDRS Part III score is that the UPDRS Part III score
shows an improvement of 3 points or more as compared with the case
where a placebo is administered, and the more expressing the effect
of improving the UPDRS Part III score is that the effect of
improving the UPDRS Part III score is significantly improved in
terms of odds ratio when the agent is administered to a patient of
Parkinson's disease where the UPDRS Part III score is 20 points or
more before the treatment with the therapeutic agent for
Parkinson's disease, as compared to the case where the agent is
administered to a patient of Parkinson's disease where the UPDRS
Part III score is less than 20 points before the treatment with the
therapeutic agent for Parkinson's disease.
28. The method according to claim 19, wherein the daily dose of
istradefylline is 20 mg or 40 mg.
29. The method according to claim 19, wherein the daily dose of
istradefylline is 40 mg.
30. The method according to claim 19, wherein the agent is
administered to a patient of Parkinson's disease during the course
of treatment with an agent containing levodopa.
Description
TECHNICAL FIELD
[0001] The present invention relates to the treatment of
Parkinson's disease using istradefylline, and the like.
BACKGROUND ART
[0002] Parkinson's disease is a brain disease characterized by
motor symptoms such as tremor, akinesia/bradykinesia, muscle
rigidity, and postural reflex disorder. The symptoms of Parkinson's
disease result from a deficiency of dopamine in part of the brain,
and most therapeutic agents for Parkinson's disease bring the
deficient amount of dopamine closer to its original state or mimic
the action of dopamine.
[0003] Levodopa (L-dopa; L-3,4-dihydroxyphenylalanine) is a
substance that is metabolized by dopa decarboxylase to become
dopamine, and was reported in 1967, but even now, more than 50
years after its discovery, it has been most used for the treatment
of Parkinson's disease. Levodopa has a strong and rapid therapeutic
effect in Parkinson's disease, however, serious and unfavorable
reactions caused by dopamine including motor complications such as
a wearing-off phenomenon, on-off fluctuations, and dyskinesias
occur.
[0004] On the other hand, istradefylline [the following Formula
(I)] is a non-dopaminergic compound having an A.sub.2A receptor
antagonistic activity and is known to be useful for the treatment
of Parkinson's disease (PTL 1), and is known to be useful for the
treatment of Parkinson's disease in combination with levodopa and
useful for the treatment of movement disorders such as motor
complications (PTL 2).
[0005] In addition, Nouriast (registered trademark) containing
istradefylline as an active ingredient was approved for manufacture
and sale in Japan in 2013 as a therapeutic agent for Parkinson's
disease, and is marketed for the indications of "improving a
wearing-off phenomenon in Parkinson's disease during the course of
treatment with a levodopa-containing preparation". Further, it was
also approved and launched in the United States in 2019.
##STR00001##
CITATION LIST
Patent Literature
[0006] PTL 1: U.S. Pat. No. 5,587,378 [0007] PTL 2: U.S. Pat. No.
7,727,993
SUMMARY OF INVENTION
Technical Problem
[0008] No analysis has been conducted yet for the fact that
istradefylline achieves more excellent effect in a patient group
having what kind of the characteristic and also for the fact that
what patient factor more favorably affects the expression of
effectiveness whereby no information has been known yet concerning
the patient background factor which much more affects the
expression of effect of istradefylline. In such a circumstance, it
has been demanded from the medical job site to actualize the
personalized medical care in the treatment of Parkinson's disease
by istradefylline.
[0009] Therefore, an object of the present invention is to provide
a means for realizing the personalized medical care in the
treatment of Parkinson's disease by istradefylline.
Solution to Problem
[0010] The present inventors considered that the personalized
medical care in the treatment of Parkinson's disease by
istradefylline can be realized by finding a specific patient
background factor corresponding to the above-mentioned factor among
a plurality of patient background factors that can be examined when
starting the treatment with istradefylline, and conducted a
combined analysis of Ph2b study and Ph3 study of istradefylline in
Japan. As a result, from the data of more than 700 patients of
Parkinson's disease, specific patient background factors that more
favorably affect the expression of effect of istradefylline was
found. The present inventors found out that by administering
istradefylline to a patient having such an individual background
factor, the expression of effect of istradefylline can be further
expected in the patient as compared with the other cases, and thus
completed the present invention.
[0011] The present invention relates to the following (1) to
(72).
[0012] (1) A therapeutic agent for Parkinson's disease containing
istradefylline as an active ingredient,
[0013] wherein the agent more expresses an effect of shortening an
OFF time when the agent is administered to a patient of Parkinson's
disease of 65 or more years old than administered to a patient of
Parkinson's disease of younger than 65 years old.
[0014] (2) The agent according to (1), wherein the more expressing
the effect of shortening the OFF time is that a rate of a patient
where the OFF time is shortened for long time is high.
[0015] (3) The agent according to (1) or (2), wherein
[0016] the effect of shortening the OFF time is that the OFF time
is shortened for 1 hour or longer as compared with the case where a
placebo is administered, and
[0017] the more expressing the effect of shortening the OFF time is
that the effect of shortening the OFF time is significantly
improved in terms of odds ratio when the agent is administered to a
patient of Parkinson's disease of 65 or more years old, as compared
to the case where the agent is administered to a patient of
Parkinson's disease of younger than 65 years old
[0018] (4) A therapeutic agent for Parkinson's disease containing
istradefylline as an active ingredient,
[0019] wherein the agent more expresses an effect of increasing an
ON time without troublesome dyskinesia when the agent is
administered to a patient of Parkinson's disease of 65 or more
years old than administered to a patient of Parkinson's disease of
younger than 65 years old.
[0020] (5) The agent according to (4), wherein the more expressing
the effect of increasing the ON time without troublesome dyskinesia
is that a rate of a patient where the ON time without troublesome
dyskinesia is extended for long time is high.
[0021] (6) The agent according to (4) or (5), wherein
[0022] the effect of increasing the ON time without troublesome
dyskinesia is that the ON time without troublesome dyskinesia is
extended for one hour or more as compared with the case when a
placebo is administered, and
[0023] the more expressing the effect of increasing the ON time
without troublesome dyskinesia is that the effect of increasing the
ON time without troublesome dyskinesia is significantly improved in
terms of odds ratio when the agent is administered to a patient of
Parkinson's disease of 65 or more years old, as compared to the
case where the agent is administered to a patient of Parkinson's
disease of younger than 65 years old.
[0024] (7) A therapeutic agent for Parkinson's disease containing
istradefylline as an active ingredient,
[0025] wherein the agent more expresses an effect of improving a
UPDRS Part III score when the agent is administered to a patient of
Parkinson's disease where the UPDRS Part III score is 20 points or
more before the treatment with the therapeutic agent for
Parkinson's disease, as compared with a patient of Parkinson's
disease where the UPDRS Part III score is less than 20 points
before the treatment with the therapeutic agent for Parkinson's
disease.
[0026] (8) The agent according to (7), wherein the more expressing
the effect of improving the UPDRS Part III score is that a rate of
a patient where the UPDRS Part III score is improved is high.
[0027] (9) The agent according to (7) or (8), wherein
[0028] the effect of improving the UPDRS Part III score is that the
UPDRS Part III score shows an improvement of 3 points or more as
compared with the case where a placebo is administered, and
[0029] the more expressing the effect of improving the UPDRS Part
III score is that the effect of improving the UPDRS Part III score
is significantly improved in terms of odds ratio when the agent is
administered to a patient of Parkinson's disease where the UPDRS
Part III score is 20 points or more before the treatment with the
therapeutic agent for Parkinson's disease, as compared to the case
where the agent is administered to a patient of Parkinson's disease
where the UPDRS Part III score is less than 20 points before the
treatment with the therapeutic agent for Parkinson's disease.
[0030] (10) A therapeutic agent for Parkinson's disease containing
istradefylline as an active ingredient,
[0031] wherein the agent more expresses an effect of improving a
UPDRS Part II score when the agent is administered to a patient of
Parkinson's disease where a m Hoehn & Yahr scale at OFF state
is 3 or more before the treatment with the therapeutic agent for
Parkinson's disease, as compared with a patient of Parkinson's
disease where the m Hoehn & Yahr scale at OFF state is less
than 3 before the treatment with the therapeutic agent for
Parkinson's disease.
[0032] (11) The agent according to (10), wherein the more
expressing the effect of improving the UPDRS Part II score is that
a rate of a patient where the UPDRS Part II score is improved is
high.
[0033] (12) The agent according to (10) or (11), wherein
[0034] the effect of improving the UPDRS Part II score is that the
UPDRS Part II score shows an improvement of 3 points or more as
compared with the case where a placebo is administered, and
[0035] the more expressing the effect of improving the UPDRS Part
II score is that the effect of improving the UPDRS Part II score is
significantly improved in terms of odds ratio when the agent is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease, as compared to
the case where the agent is administered to a patient of
Parkinson's disease where the m Hoehn & Yahr scale at OFF state
is less than 3 before the treatment with the therapeutic agent for
Parkinson's disease.
[0036] (13) A therapeutic agent for Parkinson's disease containing
istradefylline as an active ingredient,
[0037] wherein the agent more improves clinical global
impression-improvement (CGI-I) when the agent is administered to a
patient of Parkinson's disease where a m Hoehn & Yahr scale at
OFF state is 3 or more before the treatment with the therapeutic
agent for Parkinson's disease, as compared with a patient of
Parkinson's disease where the m Hoehn & Yahr scale at OFF state
is less than 3 before the treatment with the therapeutic agent for
Parkinson's disease.
[0038] (14) The agent according to (13), wherein the more improving
the CGI-I is that a rate of a patient showing "very much improved",
"much improved" or "minimally improved" in terms of the CGI-I score
is high, as compared with the case where a placebo is
administered.
[0039] (15) The agent according to (13) or (14), wherein
[0040] the improvement of the CGI-I is that a patient shows "very
much improved", "much improved" or "minimally improved" in terms of
the CGI-I score, and
[0041] the more improving the CGI-I is that the CGI-I is
significantly improved in terms of odds ratio when the agent is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease, as compared to
the case where the agent is administered to a patient of
Parkinson's disease where the m Hoehn & Yahr scale at OFF state
before the treatment with the therapeutic agent for Parkinson's
disease is less than 3.
[0042] (16) The agent according to any of (1) to (15), wherein the
daily dose of istradefylline is 20 mg or 40 mg.
[0043] (17) The agent according to any of (1) to (15), wherein the
daily dose of istradefylline is 40 mg.
[0044] (18) The agent according to any of (1) to (17), wherein the
agent is administered to a patient of Parkinson's disease during
the course of treatment with an agent containing levodopa.
[0045] (19) A method for more expressing an effect of shortening an
OFF time in treatment of Parkinson's disease as compared with the
case where a therapeutic agent for Parkinson's disease containing
istradefylline as an active ingredient is administered to a patient
of Parkinson's disease of younger than 65 years old, comprising
administering the therapeutic agent for Parkinson's disease
containing istradefylline as an active ingredient to a patient of
Parkinson's disease of 65 or more years old.
[0046] (20) The method according to (19), wherein the more
expressing the effect of shortening the OFF time is that a rate of
a patient where the OFF time is shortened for long time is
high.
[0047] (21) The method according to (19) or (20), wherein
[0048] the effect of shortening the OFF time is that the OFF time
is shortened for 1 hour or longer as compared with the case where a
placebo is administered, and
[0049] the more expressing the effect of shortening the OFF time is
that the effect of shortening the OFF time is significantly
improved in terms of odds ratio when the agent is administered to a
patient of Parkinson's disease of 65 or more years old, as compared
to the case where the agent is administered to a patient of
Parkinson's disease of younger than 65 years old.
[0050] (22) A method for more expressing an effect of increasing an
ON time without troublesome dyskinesia in treatment of Parkinson's
disease as compared with the case where a therapeutic agent for
Parkinson's disease containing istradefylline as an active
ingredient is administered to a patient of Parkinson's disease of
younger than 65 years old, comprising administering the therapeutic
agent for Parkinson's disease containing istradefylline as an
active ingredient to a patient of Parkinson's disease of 65 or more
years old.
[0051] (23) The method according to (22), wherein the more
expressing the effect of increasing the ON time without troublesome
dyskinesia in the treatment of Parkinson's disease is that a rate
of a patient where the ON time without troublesome dyskinesia is
extended for long time is high.
[0052] (24) The method according to (22) or (23), wherein
[0053] the effect of increasing the ON time without troublesome
dyskinesia is that the ON time without troublesome dyskinesia is
extended for one hour or more as compared with the case when a
placebo is administered, and
[0054] the more expressing the effect of increasing the ON time
without troublesome dyskinesia is that the effect of increasing the
ON time without troublesome dyskinesia is significantly improved in
terms of odds ratio when the agent is administered to a patient of
Parkinson's disease of 65 or more years old, as compared to the
case where the agent is administered to a patient of Parkinson's
disease of younger than 65 years old.
[0055] (25) A method for more expressing an effect of improving the
UPDRS Part III score as compared with the case where a therapeutic
agent for Parkinson's disease containing istradefylline as an
active ingredient is administered to a patient of Parkinson's
disease where a UPDRS Part III score is less than 20 points before
the treatment with the therapeutic agent for Parkinson's disease,
comprising administering the therapeutic agent for Parkinson's
disease containing istradefylline as an active ingredient to a
patient of Parkinson's disease where a UPDRS Part III score is 20
points or more before the treatment with the therapeutic agent for
Parkinson's disease.
[0056] (26) The method according to (25), wherein the more
expressing the effect of improving the UPDRS Part III score is that
a rate of a patient where the UPDRS Part III score is improved is
high.
[0057] (27) The method according to (25) or (26), wherein
[0058] the effect of improving the UPDRS Part III score is that the
UPDRS Part III score shows an improvement of 3 points or more as
compared with the case where a placebo is administered, and
[0059] the more expressing the effect of improving the UPDRS Part
III score is that the effect of improving the UPDRS Part III score
is significantly improved in terms of odds ratio when the agent is
administered to a patient of Parkinson's disease where the UPDRS
Part III score is 20 points or more before the treatment with the
therapeutic agent for Parkinson's disease, as compared to the case
where the agent is administered to a patient of Parkinson's disease
where the UPDRS Part III score is less than 20 points before the
treatment with the therapeutic agent for Parkinson's disease.
[0060] (28) A method for more expressing an effect of improving a
UPDRS Part II score as compared with the case where a therapeutic
agent for Parkinson's disease containing istradefylline as an
active ingredient is administered to a patient of Parkinson's
disease where a m Hoehn & Yahr scale at OFF state is less than
3 before the treatment with the therapeutic agent for Parkinson's
disease, comprising administering the therapeutic agent for
Parkinson's disease containing istradefylline as an active
ingredient to a patient of Parkinson's disease where a m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease.
[0061] (29) The method according to (28), wherein the more
expressing the effect of improving the UPDRS Part II score is that
a rate of a patient where the UPDRS Part II score is improved is
high.
[0062] (30) The method according to (28) or (29), wherein
[0063] the effect of improving the UPDRS Part II score is that the
UPDRS Part II score shows an improvement of 3 points or more as
compared with the case where a placebo is administered, and
[0064] the more expressing the effect of improving the UPDRS Part
II score is that the effect of improving the UPDRS Part II score is
significantly improved in terms of odds ratio when the agent is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease, as compared to
the case where the agent is administered to a patient of
Parkinson's disease where the m Hoehn & Yahr scale at OFF state
is less than 3 before the treatment with the therapeutic agent for
Parkinson's disease.
[0065] (31) A method for more improving clinical global
impression-improvement (CGI-I) as compared with the case where a
therapeutic agent for Parkinson's disease containing istradefylline
as an active ingredient is administered to a patient of Parkinson's
disease where a m Hoehn & Yahr scale at OFF state is less than
3 before the treatment with the therapeutic agent for Parkinson's
disease, comprising administering the therapeutic agent for
Parkinson's disease containing istradefylline as an active
ingredient to a patient of Parkinson's disease where a m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease.
[0066] (32) The method according to (31), wherein the more
improving the CGI-I is that a rate of a patient showing "very much
improved", "much improved" or "minimally improved" in terms of the
CGI-I score is high, as compared with the case where a placebo is
administered.
[0067] (33) The method according to (31) or (32), wherein
[0068] the improvement of the CGI-I is that a patient shows "very
much improved", "much improved" or "minimally improved" in terms of
the CGI-I score, and
[0069] the more improving the CGI-I is that the CGI-I is
significantly improved in terms of odds ratio when the agent is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease, as compared to
the case where the agent is administered to a patient of
Parkinson's disease where the m Hoehn & Yahr scale at OFF state
before the treatment with the therapeutic agent for Parkinson's
disease is less than 3.
[0070] (34) The method according to any of (19) to (33), wherein
the daily dose of istradefylline is 20 mg or 40 mg.
[0071] (35) The method according to any of (19) to (33), wherein
the daily dose of istradefylline is 40 mg.
[0072] (36) The method according to any of (19) to (35), wherein
the agent is administered to a patient of Parkinson's disease
during the course of treatment with an agent containing
levodopa.
[0073] (37) Use of istradefylline or a pharmacologically acceptable
salt thereof for more expressing an effect of shortening an OFF
time in the treatment of Parkinson's disease by administration to a
patient of Parkinson's disease of 65 or more years old as compared
with the case where it is administered to a patient of Parkinson's
disease of younger than 65 years old.
[0074] (38) The use according to (37), wherein the more expressing
the effect of shortening the OFF time is that a rate of a patient
where the OFF time is shortened for long time is high.
[0075] (39) The use according to (37) or (38), wherein
[0076] the effect of shortening the OFF time is that the OFF time
is shortened for 1 hour or longer as compared with the case where a
placebo is administered, and
[0077] the more expressing the effect of shortening the OFF time is
that the effect of shortening the OFF time is significantly
improved in terms of odds ratio when it is administered to a
patient of Parkinson's disease of 65 or more years old, as compared
to the case where it is administered to a patient of Parkinson's
disease of younger than 65 years old.
[0078] (40) Use of istradefylline or a pharmacologically acceptable
salt thereof for more expressing an effect of increasing an ON time
without troublesome dyskinesia in the treatment of Parkinson's
disease by administration to a patient of Parkinson's disease of 65
or more years old as compared with the case where it is
administered to a patient of Parkinson's disease of younger than 65
years old.
[0079] (41) The use according to (40), wherein the more expressing
the effect of increasing the ON time without troublesome dyskinesia
is that a rate of a patient where the ON time without troublesome
dyskinesia is extended for long time is high.
[0080] (42) The use according to (40) or (41), wherein
[0081] the effect of increasing the ON time without troublesome
dyskinesia is that the ON time without troublesome dyskinesia is
extended for one hour or more as compared with the case when a
placebo is administered, and
[0082] the more expressing the effect of increasing the ON time
without troublesome dyskinesia is that the effect of increasing the
ON time without troublesome dyskinesia is significantly improved in
terms of odds ratio when it is administered to a patient of
Parkinson's disease of 65 or more years old, as compared to the
case where it is administered to a patient of Parkinson's disease
of younger than 65 years old.
[0083] (43) Use of istradefylline or a pharmacologically acceptable
salt thereof for more expressing an effect of improving a UPDRS
Part III score by administration to a patient of Parkinson's
disease where the UPDRS Part III score before treatment is 20
points or more as compared with the case where it is administered
to a patient of Parkinson's disease where the UPDRS Part III score
before treatment is less than 20 points.
[0084] (44) The use according to (43), wherein the more expressing
the effect of improving the UPDRS Part III score is that a rate of
a patient where the UPDRS Part III score is improved is high.
[0085] (45) The use according to (43) or (44), wherein
[0086] the effect of improving the UPDRS Part III score is that the
UPDRS Part III score shows an improvement of 3 points or more as
compared with the case where a placebo is administered, and
[0087] the more expressing the effect of improving the UPDRS Part
III score is that the effect of improving the UPDRS Part III score
is significantly improved in terms of odds ratio when it is
administered to a patient of Parkinson's disease where the UPDRS
Part III score is 20 points or more before the treatment with the
therapeutic agent for Parkinson's disease, as compared to the case
where it is administered to a patient of Parkinson's disease where
the UPDRS Part III score is less than 20 points before the
treatment with the therapeutic agent for Parkinson's disease.
[0088] (46) Use of istradefylline or a pharmacologically acceptable
salt thereof for more expressing an effect of improving a UPDRS
Part II score by administration to a patient of Parkinson's disease
where a m Hoehn & Yahr scale at OFF state before treatment is 3
or more as compared with the case where it is administered to a
patient of Parkinson's disease where the m Hoehn & Yahr scale
at OFF state before treatment is less than 3.
[0089] (47) The use according to (46), wherein the more expressing
the effect of improving the UPDRS Part II score is that a rate of a
patient where the UPDRS Part II score is improved is high.
[0090] (48) The use according to (46) or (47), wherein
[0091] the effect of improving the UPDRS Part II score is that the
UPDRS Part II score shows an improvement of 3 points or more as
compared with the case where a placebo is administered, and
[0092] the more expressing the effect of improving the UPDRS Part
II score is that the effect of improving the UPDRS Part II score is
significantly improved in terms of odds ratio when it is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale score at OFF state is 3 or more before the
treatment with the therapeutic agent for Parkinson's disease, as
compared to the case where it is administered to a patient of
Parkinson's disease where the m Hoehn & Yahr scale at OFF state
is less than 3 before the treatment with the therapeutic agent for
Parkinson's disease.
[0093] (49) Use of istradefylline or a pharmacologically acceptable
salt thereof for more improving clinical global
impression-improvement (CGI-I) by administration to a patient of
Parkinson's disease where a m Hoehn & Yahr scale at OFF state
before treatment is 3 or more as compared with the case where it is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale at OFF state before treatment is less than 3.
[0094] (50) The use according to (49), wherein the more improving
the CGI-I is that a rate of a patient showing "very much improved",
"much improved" or "minimally improved" in terms of the CGI-I score
is high, as compared with the case where a placebo is
administered.
[0095] (51) The use according to (49) or (50), wherein
[0096] the improvement of the CGI-I is that a patient shows "very
much improved", "much improved" or "minimally improved" in terms of
the CGI-I score, and
[0097] the more improving the CGI-I is that the CGI-I is
significantly improved in terms of odds ratio when it is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease, as compared to
the case where it is administered to a patient of Parkinson's
disease where the m Hoehn & Yahr scale at OFF state before the
treatment with the therapeutic agent for Parkinson's disease is
less than 3.
[0098] (52) The use according to any of (37) to (51), wherein the
daily dose of istradefylline is 20 mg or 40 mg.
[0099] (53) The use according to any of (37) to (51), wherein the
daily dose of istradefylline is 40 mg.
[0100] (54) The use according to any of (37) to (53), wherein the
administration is performed to a patient of Parkinson's disease
during the course of treatment with an agent containing
levodopa.
[0101] (55) Use of istradefylline or a pharmacologically acceptable
salt thereof for manufacture of a therapeutic agent for more
expressing an effect of shortening an OFF time in the treatment of
Parkinson's disease by administration to a patient of Parkinson's
disease of 65 or more years old as compared with the case where it
is administered to a patient of Parkinson's disease of younger than
65 years old.
[0102] (56) The use according to (55), wherein the more expressing
the effect of shortening the OFF time is that a rate of a patient
where the OFF time is shortened for long time is high.
[0103] (57) The use according to (55) or (56), wherein
[0104] the effect of shortening the OFF time is that the OFF time
is shortened for 1 hour or longer as compared with the case where a
placebo is administered, and
[0105] the more expressing the effect of shortening the OFF time is
that the effect of shortening the OFF time is significantly
improved in terms of odds ratio when it is administered to a
patient of Parkinson's disease of 65 or more years old, as compared
to the case where it is administered to a patient of Parkinson's
disease of younger than 65 years old.
[0106] (58) Use of istradefylline or a pharmacologically acceptable
salt thereof for manufacture of a therapeutic agent for more
expressing an effect of increasing an ON time without troublesome
dyskinesia in the treatment of Parkinson's disease by
administration to a patient of Parkinson's disease of 65 or more
years old as compared with the case where it is administered to a
patient of Parkinson's disease of younger than 65 years old.
[0107] (59) The use according to (58), wherein the more expressing
the effect of increasing the ON time without troublesome dyskinesia
is that a rate of a patient where the ON time without troublesome
dyskinesia is extended for long time is high.
[0108] (60) The use according to (58) or (59), wherein
[0109] the effect of increasing the ON time without troublesome
dyskinesia is that the ON time without troublesome dyskinesia is
extended for one hour or more as compared with the case when a
placebo is administered, and
[0110] the more expressing the effect of increasing the ON time
without troublesome dyskinesia is that the effect of increasing the
ON time without troublesome dyskinesia is significantly improved in
terms of odds ratio when it is administered to a patient of
Parkinson's disease of 65 or more years old, as compared to the
case where it is administered to a patient of Parkinson's disease
of younger than 65 years old.
[0111] (61) Use of istradefylline or a pharmacologically acceptable
salt thereof for manufacture of a therapeutic agent for more
expressing an effect of improving a UPDRS Part III score by
administration to a patient of Parkinson's disease where the UPDRS
Part III score before treatment is 20 points or more as compared
with the case where it is administered to a patient of Parkinson's
disease where the UPDRS Part III score before treatment is less
than 20 points.
[0112] (62) The use according to (61), wherein the more expressing
the effect of improving the UPDRS Part III score is that a rate of
a patient where the UPDRS Part III score is improved is high.
[0113] (63) The use according to (61) or (62), wherein
[0114] the effect of improving the UPDRS Part III score is that the
UPDRS Part III score shows an improvement of 3 points or more as
compared with the case where a placebo is administered, and
[0115] the more expressing the effect of improving the UPDRS Part
III score is that the effect of improving the UPDRS Part III score
is significantly improved in terms of odds ratio when it is
administered to a patient of Parkinson's disease where the UPDRS
Part III score is 20 points or more before the treatment with the
therapeutic agent for Parkinson's disease, as compared to the case
where it is administered to a patient of Parkinson's disease where
the UPDRS Part III score is less than 20 points before the
treatment with the therapeutic agent for Parkinson's disease.
[0116] (64) Use of istradefylline or a pharmacologically acceptable
salt thereof for manufacture of a therapeutic agent for more
expressing an effect of improving a UPDRS Part II score by
administration to a patient of Parkinson's disease where a m Hoehn
& Yahr scale at OFF state before treatment is 3 or more as
compared with the case where it is administered to a patient of
Parkinson's disease where the m Hoehn & Yahr scale at OFF state
before treatment is less than 3.
[0117] (65) The use according to (64), wherein the more expressing
the effect of improving the UPDRS Part II score is that a rate of a
patient where the UPDRS Part II score is improved is high.
[0118] (66) The use according to (64) or (65), wherein
[0119] the effect of improving the UPDRS Part II score is that the
UPDRS Part II score shows an improvement of 3 points or more as
compared with the case where a placebo is administered, and
[0120] the more expressing the effect of improving the UPDRS Part
II score is that the effect of improving the UPDRS Part II score is
significantly improved in terms of odds ratio when it is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease, as compared to
the case where it is administered to a patient of Parkinson's
disease where the m Hoehn & Yahr scale at OFF state is less
than 3 before the treatment with the therapeutic agent for
Parkinson's disease.
[0121] (67) Use of istradefylline or a pharmacologically acceptable
salt thereof for manufacture of a therapeutic agent for more
improving clinical global impression-improvement (CGI-I) by
administration to a patient of Parkinson's disease where a m Hoehn
& Yahr scale at OFF state before treatment is 3 or more as
compared with the case where it is administered to a patient of
Parkinson's disease where the m Hoehn & Yahr scale at OFF state
before treatment is less than 3.
[0122] (68) The use according to (67), wherein the more improving
the CGI-I is that a rate of a patient showing "very much improved",
"much improved" or "minimally improved" in terms of the CGI-I score
is high, as compared with the case where a placebo is
administered.
[0123] (69) The use according to (67) or (68), wherein
[0124] the improvement of the CGI-I is that a patient shows "very
much improved", "much improved" or "minimally improved" in terms of
the CGI-I score, and
[0125] the more improving the CGI-I is that the CGI-I is
significantly improved in terms of odds ratio when it is
administered to a patient of Parkinson's disease where the m Hoehn
& Yahr scale at OFF state is 3 or more before the treatment
with the therapeutic agent for Parkinson's disease, as compared to
the case where it is administered to a patient of Parkinson's
disease where the m Hoehn & Yahr scale at OFF state before the
treatment with the therapeutic agent for Parkinson's disease is
less than 3.
[0126] (70) The use according to any of (55) to (69), wherein the
daily dose of istradefylline is 20 mg or 40 mg.
[0127] (71) The use according to any of (55) to (69), wherein the
daily dose of istradefylline is 40 mg.
[0128] (72) The use according to any of (55) to (71), wherein the
administration is performed to a patient of Parkinson's disease
during the course of treatment with an agent containing
levodopa.
Advantageous Effects of Invention
[0129] According to the present invention, a therapeutic agent for
Parkinson's disease containing istradefylline as an active
ingredient for a specific patient group having a background factor
that allows the treatment of Parkinson's disease using
istradefylline to more express an effect, a method for
administering a therapeutic agent for Parkinson's disease
containing istradefylline as an active ingredient to a specific
patient group having a background factor that allows the treatment
of Parkinson's disease using istradefylline to more express an
effect, and the like can be provided.
DESCRIPTION OF EMBODIMENTS
[0130] Parkinson's disease is a chronically progressive
neurodegenerative disease and is characterized by four major motor
signs: resting tremor, muscle rigidity, akinesia, and postural
reflex disorder. With selective degeneration and shedding of
dopamine neurons that project from the midbrain substantia nigra to
the striatum, dopamine in the striatum is significantly reduced and
depleted, which is considered to be the cause of the onset of
Parkinson's disease symptoms.
[0131] Levodopa is a precursor of a neurotransmitter dopamine, and
reaches the central nervous system by peripheral administration.
After being taken up by neurons in the brain, it is converted to
dopamine by a metabolic enzyme (dopa decarboxylase). Levodopa was
developed as a therapeutic agent for Parkinson's disease for the
purpose of replenishing the reduction in dopamine in the striatum
in Parkinson's disease.
[0132] A levodopa-containing preparation is a preparation
containing levodopa as an active ingredient, and is a preparation
designed for the purpose of inhibiting the peripheral metabolism of
levodopa and increasing the utilization rate in the central nervous
system. For example, a two-drug combination with carbidopa or
benserazide being a peripheral dopa decarboxylase inhibitor, a
three-drug combination, in which entacapone being a peripheral
catechol O-methyltransferase inhibitor is further added, and the
like are available.
[0133] UPDRS (Unified Parkinson's Disease Rating Scale) is one of
the evaluation indexes of Parkinson's disease. The UPDRS is
composed of Part I to IV, and is divided into Part I: non-motor
experiences of daily living, Part II: motor experiences of daily
living, Part III: motor examination, and Part IV: motor
complications.
[0134] With respect to "ON" and "OFF" in the treatment of
Parkinson's disease, a state in which the effect of a therapeutic
agent for Parkinson's disease is observed is defined as "ON", and a
state in which the effect is not observed is defined as "OFF". The
"OFF" includes phenomena that appear when treatment is performed
with a levodopa-containing preparation, such as a wearing-off
phenomenon in which the effect of the drug related to motor
symptoms does not last, and an on-off phenomenon in which the
effect of the drug suddenly diminishes or disappears, or suddenly
appears.
[0135] The m Hoehn & Yahr scale (modified Hoehn and Yahr Scale)
is used as an index indicating the degree of progression (severity)
of Parkinson's disease. The m Hoehn & Yahr scale is a scale
represented by 8 stages in which stage 0, stage 1.5, and stage 2.5
are added to the original Hoehn & Yahr scale represented by 5
stages from stage 1 to stage 5 (stage 0: no parkinsonism, stage 1:
unilateral parkinsonism, stage 1.5: unilateral parkinsonism and
truncal ataxia, stage 2: bilateral parkinsonism but no impairment
of balance, stage 2.5: mild bilateral parkinsonism and retropulsion
but recovers by oneself, stage 3: mild to moderate bilateral
parkinsonism and impairment of balance, no assistance required,
stage 4: severe parkinsonism and impairment of balance, still able
to walk without assistance, and stage 5: wheelchair bound or
bedridden unless aided, difficult to walk even with
assistance).
[0136] The Clinical global impression-improvement (CGI-I) is a
7-point global clinical rating scale (also referred to as a CGI-I
score) shown below for evaluating the clinical global improvement.
A physician makes a determination by comparison with that at
baseline. The 7-point clinical rating scale is composed of: Very
much improved, Much improved, Minimally improved, No change,
Minimally worse, Much worse, and Very much worse.
EXAMPLES
[0137] 1. Methods
[0138] 1.1. Patient Population and Study Design
[0139] A pooled analysis was performed for two clinical studies of
istradefylline combined with L-DOPA previously conducted in Japan.
Both studies were performed according to the principles of the
Declaration of Helsinki and were identically designed for 12-week,
multicenter, randomized, double-blind, placebo-controlled, and
parallel-group studies approved by the relevant institutional
review boards of each center [(i) Mizuno Y, Kondo T. Adenosine
A.sub.2A receptor antagonist istradefylline reduces daily OFF time
in Parkinson's disease. Mov Disord 2013; 28: 1138-41, and (ii)
Mizuno Y, Hasegawa K, Kondo T, et al. Clinical efficacy of
istradefylline (KW-6002) in Parkinson's disease: a randomized,
controlled study. Mov Disord 2010; 25(10): 1437-43)]. Both studies
were registered in ClinicalTrials.gov (NCT00455507 [phase 2b] and
NCT00955526 [phase 3]). Both studies enrolled patients of
Parkinson's disease who were experiencing motor fluctuations.
[0140] Key inclusion criteria included age 20 years, stages 2-4
(OFF state) based on the Modified Hoehn and Yahr (mH&Y) scale,
stable treatment regimen of antiparkinsonian drugs, and motor
fluctuations with an OFF time of 2 hours or longer per day. Key
exclusion criteria included history of surgical operation for
Parkinson's disease, cognitive impairment, and pregnancy. The study
protocols were approved by the institutional review boards at all
participating study sites, and written informed consent was
obtained from all patients prior to participation.
[0141] In both studies, eligible subjects were randomized to one of
three groups: 12-week istradefylline 20 mg/day group, 12-week
istradefylline 40 mg/day group, and 12-week placebo group. The
subjects attended site visits at weeks 2, 4, 8, and 12 after
randomization, and submitted patient diaries covering the 7-day
period prior to each visit. The full analysis set included subjects
who received at least one dose of study drug and completed at least
one set of patient diaries.
[0142] 1.2. Efficacy Outcomes
[0143] The primary outcomes were changes in OFF time (hours/day)
from baseline to 12 weeks obtained from the patient diaries, which
were compared between the placebo group and the istradefylline
group. Other outcomes included changes (%) in daily OFF time,
changes in ON time without troublesome dyskinesia ("Good" ON time)
(Hauser RA, Deckers F, Lehert P. Parkinson's disease home diary:
further validation and implications for clinical trials. Mov Disord
2004; 19(12): 1409-13), (which was the summation of ON time without
dyskinesia and ON time with non-troublesome dyskinesia), UPDRS
parts I-IV score, and changes in Clinical Global
Impressions-Improvement (CGI-I) score from baseline to 12 weeks.
The varying from baseline values, and the treatment effect were
determined as a difference in mean change between the placebo group
and the istradefylline group during the follow up period.
[0144] 1.3. Definition of Cut-Off Value for Efficacy Outcomes
[0145] The cut-off value for the treatment effect used to determine
the efficacy of istradefylline was defined as a reduction in OFF
time (1 hour or longer), an increase in ON time without troublesome
dyskinesia (1 hour or longer), and an improvement in UPDRS Part III
score (3 points or more) from the clinically meaningful point of
view. Data distribution of each parameter is comparable, and
therefore, the cut off value was defined as a value obtained by
subtracting the placebo effect (Hauser RA, Auinger P. Determination
of Minimal Clinically Important Change in Early and Advanced
Parkinson's Disease. Movement Disorders 2011; 26:813-8). In
addition, with respect to the CGI-I score, "very much improved",
"much improved", and "minimally improved" were determined to be
effective. Further, with respect to the UPDRS Part II score at OFF
state, an improvement of 1 point or more from the
sensitivity/(1-specificity) curve (ROC curve) using the UPDRS Part
II score and the CGI-I score was defined as the cut-off of the
effect.
[0146] 1.4. Statistical Analysis
[0147] Baseline data were summarized for all and respective
treatment groups (placebo and istradefylline: 20 mg or 40 mg).
Continuous variables were expressed as mean and standard deviation
(SD), whereas categorical variables were expressed as proportions.
The following statistical analyses were performed for patients
without any missing data (listwise deletion or complete case
analysis).
[0148] The study of baseline factors having a favorable effect on
the respective outcomes of the efficacy of istradefylline was
performed by multivariate logistic regression analysis controlling
for 12 baseline factors, which were expressed as the odds ratio
(OR) and 95% confidence interval (CI). The efficacy outcomes
included daily OFF time, ON time without troublesome dyskinesia,
UPDRS Part III score at ON state, CGI-I, and UPDRS Part II score at
OFF state. As covariates in the logistic regression analysis, age,
sex, the presence or absence of dyskinesia history (determined
based on the patient diary at baseline), mean daily OFF time, total
UPDRS Part III score, mH&Y score at ON state and OFF state,
concomitant drugs, duration of Parkinson's disease (duration of
PD), duration of motor complications, L-DOPA dose, and
levodopa-equivalent dose were used.
[0149] In this study, with respect to the outcomes under the
treatment with istradefylline, analysis of baseline factors
associated with expressing a more favorable effect was performed
according to the following three steps. First, interactions between
the treatment with istradefylline (two doses: 20 mg and 40 mg) and
12 baseline factors were evaluated based on type III p-value by
multivariate logistic regression analysis (an index for evaluating
whether or not the heterogeneity (interaction) occurs in the
association between the treatment and the outcome due to a certain
baseline factor). As the second step, an odds ratio (OR) was
estimated for the baseline factor associated with the achievement
of a more favorable effect according to the dose group of
istradefylline if a significant interaction is observed between the
treatment with istradefylline and the baseline factor. In addition,
OR was estimated for the baseline factor associated with the
achievement of a more favorable effect in all patient groups if an
interaction is not observed between the treatment with
istradefylline and the baseline factor.
[0150] Further, construction of prognosis prediction models was
performed for each of two outcomes (OFF time and ON time without
troublesome dyskinesia) as exploratory analysis using the candidate
baseline factors obtained by referring to the results of the
multivariate logistic regression analysis. The prognosis prediction
performance of the models was evaluated by area under the curve
(AUC, Mann-Whitney U-statistic) of ROC curves.
[0151] A two-tailed p value <0.05 and an interaction p value
<0.10 were determined to be statistically significant. All
analyses were performed using SAS software version 9.2 or 9.3 (SAS
Institute, Inc., Cary, N.C., USA).
[0152] 2. Results
[0153] 2.1. Patients
[0154] In the phase 2b study, a total of 363 eligible patients were
randomized and the full analysis set (FAS) included 357 patients.
In the phase 3 study, a total of 373 eligible patients were
randomized and the FAS included 366 patients. The total pooled FAS
included 723 patients (placebo, n=241; istradefylline 20 mg/day,
n=235; and istradefylline 40 mg/day, n=247). The demographic and
baseline information for the pooled patient population is
summarized in Table 1. Most patient demographic and baseline
factors in the treatment groups were comparable within the phase 2b
study and the phase 3 study, except for concomitant
anti-Parkinson's disease drugs used at baseline because zonisamide
was not available during the phase 2b study.
[0155] 2.2. Effect
[0156] The overall efficacy of istradefylline is summarized in
Table 2 as the change from baseline associated with each treatment
group for each outcome. Distribution of data on OFF time in each
treatment group is comparable between groups.
[0157] As compared with the placebo group, both dose groups of
istradefylline (20 mg/day and 40 mg/day) showed significant
reductions in daily OFF time [mean daily OFF time (hours)], daily
percentage of OFF time [mean daily OFF time (%)], UPDRS Part III
score (ON state) (UPDRS Part III score at ON state), and UPDRS
Parts I-III score (ON state) (total UPDRS Parts I-III score at ON
state). Further, the istradefylline 40 mg/day group showed
significant reductions in UPDRS Part II score (OFF state) and UPDRS
Part IV score.
[0158] Both dose groups of istradefylline significantly increased
ON time without dyskinesia [mean daily ON time (hours) without
dyskinesia], ON time with non-troublesome dyskinesia [mean daily ON
time (hours) with non-troublesome dyskinesia], ON time without
troublesome dyskinesia [mean daily ON time (hours) without
troublesome dyskinesia], percentage of ON time without dyskinesia
[mean daily percentage of ON time (%) without dyskinesia],
percentage of ON time with non-troublesome dyskinesia [mean daily
percentage of ON time (%) with non-troublesome dyskinesia], and
percentage of ON time without troublesome dyskinesia [mean daily
percentage of ON time (%) without troublesome dyskinesia].
[0159] 2.3. Association Between Efficacy and Patient Baseline
Factors by Multivariate Logistic Regression Analysis
[0160] The patient baseline factors associated with five efficacy
outcomes (OFF time reduction, increase in ON time without
troublesome dyskinesia, improvement in UPDRS Part II score [OFF
state], improvement in UPDRS Part III score, and CGI-I score) and
interaction factors (age, mean daily OFF time, total UPDRS Part III
score, and mH&Y scale [ON state and OFF state]) under the
treatment with istradefylline were studied. The results of the
respective outcomes [OFF time, ON time without troublesome
dyskinesia, UPDRS Part III score, UPDRS Part II score (OFF state),
and CGI-I score] are shown in Table 3 (items 2.3.1 to 2.3.4).
[0161] 2.3.1. OFF Time Reduction
[0162] A reduction in OFF time was observed with istradefylline
treatment, and this effect was found to be significantly greater in
patients of 65 or more years old as compared with patients of
younger than 65 years old (odds ratio: 2.65). Also, patients with a
higher mean baseline OFF time showed a significantly greater
reduction in OFF time with istradefylline at a dose of 40 mg/day as
compared with the case of istradefylline at a dose of 20 mg/day or
patients with a lower mean baseline OFF time. The effect of
istradefylline at 40 mg/day on OFF time reduction was most
favorably observed in patients with an OFF time of 8 hours or
longer at baseline (odds ratio: 6.68).
[0163] 2.3.2. Increase in ON Time without Troublesome
Dyskinesia
[0164] In patients of 65 or more years old at baseline, a favorable
improvement by istradefylline was observed, and the ON time without
troublesome dyskinesia increased as compared with patients of
younger than 65 years old, and in particular, a significant
association was observed in the group treated with istradefylline
at 40 mg/day (odds ratio: 2.88).
[0165] 2.3.3. Improvement in UPDRS Part III Score
[0166] The total UPDRS Part III score at baseline was associated
with a favorable improvement in UPDRS Part III score by
istradefylline treatment. The effect of istradefylline on the
improvement in UPDRS Part III score was greater in patients with a
total UPDRS Part III score at baseline of 20 points or more as
compared with patients with a total UPDRS Part III score at
baseline less than 20 points (odds ratio: 2.79). A dose-related
effect of istradefylline (20 mg/day or 40 mg/day) was observed for
L-DOPA dose, LED, the presence or absence of dyskinesia, and
mH&Y stage (OFF state), but the effect was not significant.
[0167] 2.3.4. Improvement in UPDRS Part II Score (OFF State) and
CGI-I Score
[0168] Istradefylline at 40 mg/day had a greater effect in patients
with a mH&Y scale (OFF state) at baseline of 3 points or more
as compared with patients with less than 3 points (odds ratio:
3.50). In addition, the mH&Y scale (OFF state) was found to be
associated with a favorable improvement in CGI-I by istradefylline
treatment; this effect was more significant in patients with a
mH&Y scale (OFF state) of 3 points or more (odds ratio: 1.89).
The baseline factors associated with a favorable improvement in
CGI-I tended to be similar to those related to UPDRS Part II (OFF
state). Since motor symptoms at the patient's office visit is
thought to affect the physician's impression, the improvement in
CGI-I is considered to be associated with the improvement in UPDRS
Part III score. However, in this study, the UPDRS Part II (OFF
state) score was also found to be associated with the improvement
in CGI-I.
TABLE-US-00001 TABLE 1 Demographic and baseline characteristics
Istradefylline group Placebo group 20 mg/day 40 mg/day Total
Characteristic N = 241 N = 235 N = 247 N = 482 Age, (y) 65.4 .+-.
8.1 65.6 .+-. 8.0 64.7 .+-. 8.8 65.1 .+-. 8.4 Sex Male (%) 103
(42.7) 90 (38.3) 119 (48.2) 209 (43.4) Female (%) 138 (57.3) 145
(61.7) 128 (51.8) 273 (56.6) Concomitant anti-PD drug, (number of
patients, % in parentheses) DA 217 (90.0) 213 (90.6) 217 (87.9) 430
(89.2) Anticholinergic drug 43 (17.8) 30 (12.8) 42 (17.0) 72 (14.9)
SEL 119 (49.4) 109 (46.4) 142 (57.5) 251 (52.1) ENT 67 (27.8) 85
(36.2) 84 (34.0) 169 (35.1) AMA 94 (39.0) 84 (35.7) 83 (33.6) 167
(34.6) ZNS 17 (7.1) 13 (5.5) 20 (8.1) 33 (6.8) Combinations of
concomitant anti-PD drugs, (number of patients, % in parentheses)
L-DOPA, L-DOPA + DA 51 (26.0) 44 (23.2) 50 (24.6) 94 (23.9) L-DOPA
+ DA + SEL/ENT/ZNS 87 (44.4) 97 (51.1) 98 (48.3) 195 (49.6) L-DOPA
+ DA + SEL/ENT/ZNS + AMA 58 (29.6) 49 (25.8) 55 (27.1) 104 (26.5)
Duration of PD, (y) 8.161 .+-. 4.633 7.661 .+-. 4.150 7.911 .+-.
4.299 7.789 .+-. 4.225 Duration of motor complications, (y) 3.468
.+-. 3.249 3.175 .+-. 2.629 3.192 .+-. 2.942 3.184 .+-. 2.791
L-DOPA dose, (mg) 425.8 .+-. 144.5 419.1 .+-. 137.3 417.9 .+-.
145.9 418.5 .+-. 141.6 L-DOPA-equivalent dose, (mg) 772.6 .+-.
278.3 740.8 .+-. 250.5 731.3 .+-. 268.6 735.9 .+-. 259.7 Mean daily
OFF time, (h) 6.37 .+-. 2.59 6.67 .+-. 2.79 6.26 .+-. 2.48 6.46
.+-. 2.64 Mean daily percentage of OFF time, (%) 39.20 .+-. 15.44
40.82 .+-. 16.13 38.36 .+-. 15.18 39.56 .+-. 15.68 Mean daily ON
time, (h) Without dyskinesia 8.07 .+-. 3.20 7.86 .+-. 3.42 8.26
.+-. 3.53 8.07 .+-. 3.48 With dyskinesia 1.77 .+-. 2.89 1.71 .+-.
2.97 1.89 .+-. 3.26 1.80 .+-. 3.12 With non-troublesome dyskinesia
1.22 .+-. 2.20 1.13 .+-. 2.02 1.23 .+-. 2.28 1.18 .+-. 2.15 With
troublesome dyskinesia 0.54 .+-. 1.30 0.58 .+-. 1.48 0.66 .+-. 1.52
0.620 .+-. 1.50 Without troublesome dyskinesia 9.28 .+-. 2.63 9.00
.+-. 2.80 9.49 .+-. 2.81 9.25 .+-. 2.81 Mean daily percentage of ON
time, (%) Without dyskinesia 49.82 .+-. 19.29 48.61 .+-. 21.17
50.32 .+-. 20.88 49.49 .+-. 21.02 With dyskinesia 10.99 .+-. 17.93
10.58 .+-. 18.35 11.33 .+-. 19.28 10.97 .+-. 18.82 With
non-troublesome dyskinesia 7.62 .+-. 13.72 6.92 .+-. 12.22 7.41
.+-. 13.49 7.17 .+-. 12.88 With troublesome dyskinesia 3.37 .+-.
8.06 3.66 .+-. 9.62 3.93 .+-. 9.01 3.80 .+-. 9.30 Without
troublesome dyskinesia 57.45 .+-. 15.72 55.53 .+-. 17.09 57.72 .+-.
15.86 56.66 .+-. 16.49 UPDRS Part I score 1.0 .+-. 1.4 1.1 .+-. 1.3
1.1 .+-. 1.4 1.1 .+-. 1.3 UPDRS Part II score ON state 6.1 .+-. 5.2
5.5 .+-. 4.9 5.7 .+-. 5.0 5.6 .+-. 4.9 OFF state 15.2 .+-. 7.4 15.3
.+-. 7.3 15.6 .+-. 7.7 15.5 .+-. 7.5 UPDRS Part III score at ON
state 21.1 .+-. 10.5 21.2 .+-. 10.7 20.9 .+-. 11.0 21.0 .+-. 10.8
UPDRS Part IV score 4.9 .+-. 2.1 5.0 .+-. 2.0 5.1 .+-. 2.4 5.1 .+-.
2.2 Total UPDRS Parts I-III score at ON state 28.3 .+-. 14.5 27.8
.+-. 14.1 27.7 .+-. 14.7 27.7 .+-. 14.4 m Hoehn & Yahr scale at
ON state, (number of patients, % in parentheses) 0 1 (0.4) 2 (0.9)
2 (0.8) 4 (0.8) 1 15 (6.3) 9 (3.9) 11 (4.5) 20 (4.2) 1.5 6 (2.5) 6
(2.6) 12 (4.9) 18 (3.8) 2 87 (36.6) 85 (36.5) 90 (36.6) 175 (36.5)
2.5 61 (25.6) 60 (25.8) 63 (25.6) 123 (25.7) 3 60 (25.2) 61 (26.2)
61 (24.8) 122 (25.5) 4 8 (3.4) 10 (4.3) 7 (2.8) 17 (3.5) 5 0 (0.0)
0 (0.0) 0 (0.0) 0 (0.0) m Hoehn & Yahr scale at OFF state,
(number of patients, % in parentheses) 0 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) 1 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1.5 0 (0.0) 0 (0.0) 0 (0.0)
0 (0.0) 2 13 (5.5) 14 (6.0) 17 (6.9) 31 (6.5) 2.5 31 (13.0) 27
(11.6) 30 (12.2) 57 (11.9) 3 113 (47.5) 100 (42.9) 101 (41.1) 201
(42.0) 4 81 (34.0) 92 (39.5) 98 (39.8) 190 (39.7) 5 0 (0.0) 0 (0.0)
0 (0.0) 0 (0.0) Data presented as mean .+-. standard deviation or
number of patients (%). DA = dopamine agonist; SEL = selegiline;
ENT = entacapone; AMA = amantadine; ZNS = zonisamide; L-DOPA =
levodopa; PD = Parkinson's disease; UPDRS = Unified Parkinson's
Disease Rating Scale
TABLE-US-00002 TABLE 2 Change from baseline to week 12 for each
endpoint and CGI-I at week 12 Istradefylline group Placebo group 20
mg/day 40 mg/day Characteristic N = 241 N = 235 N = 247 Mean daily
OFF time, (h) -0.45 .+-. 2.25 -1.23 .+-. 1.97 -1.27 .+-. 2.42 (p
< 0.0001) (p < 0.0001) Mean daily percentage of OFF time, (%)
-2.75 .+-. 13.88 -7.62 .+-. 12.62 -7.76 .+-. 15.02 (p < 0.0001)
(p < 0.0001) Mean daily ON time, (h) Without dyskinesia 0.41
.+-. 2.58 1.03 .+-. 2.20 0.99 .+-. 2.86 (p = 0.0020) (p = 0.0053)
With dyskinesia -0.05 .+-. 1.70 0.19 .+-. 1.53 0.20 .+-. 1.93 (p =
0.9926) (p = 0.9990) With non-troublesome dyskinesia 0.03 .+-. 1.45
0.16 .+-. 1.56 0.15 .+-. 1.36 (p = 0.0287) (p = 0.0496) With
troublesome dyskinesia -0.07 .+-. 0.84 0.03 .+-. 1.33 0.06 .+-.
1.13 (p = 0.9231) (p = 0.9868) Without troublesome dyskinesia 0.45
.+-. 2.46 1.19 .+-. 2.44 1.13 .+-. 2.65 (p = 0.0002) (p = 0.0007)
Mean daily percentage of ON time, (%) Without dyskinesia 2.90 .+-.
15.85 6.28 .+-. 13.68 6.46 .+-. 17.10 (p = 0.0050) (p = 0.0085)
With dyskinesia -0.16 .+-. 10.48 1.32 .+-. 9.36 1.28 .+-. 11.40 (p
= 0.9817) (p = 0.9939) With non-troublesome dyskinesia 0.23 .+-.
8.91 1.17 .+-. 9.54 0.92 .+-. 8.26 (p = 0.0442) (p = 0.0910) With
troublesome dyskinesia -0.39 .+-. 5.29 0.15 .+-. 8.12 0.36 .+-.
6.44 (p = 0.8890) (p = 0.9832) Without troublesome dyskinesia 3.13
.+-. 14.97 7.45 .+-. 14.95 7.39 .+-. 15.73 (p = 0.0005) (p =
0.0013) UPDRS Part I score -0.1 .+-. 0.7 -0.2 .+-. 0.9 -0.1 .+-.
1.0 (p = 0.2729) (p = 0.4129) UPDRS Part II score ON state -0.6
.+-. 1.7 -0.5 .+-. 2.3 -0.7 .+-. 2.2 (p = 0.5691) (p = 0.3266) OFF
state -1.3 .+-. 3.2 -1.8 .+-. 4.1 -2.0 .+-. 3.8 (p = 0.0698) (p =
0.0259) UPDRS Part III score at ON state -3.5 .+-. 5.3 -5.1 .+-.
7.2 -5.5 .+-. 6.6 (p = 0.0168) (p = 0.0010) UPDRS Part IV score
-0.2 .+-. 1.3 -0.1 .+-. 1.6 -0.5 .+-. 1.6 (p = 0.4071) (p = 0.0110)
Total UPDRS Parts I-III at ON state -4.3 .+-. 6.2 -5.8 .+-. 8.6
-6.3 .+-. 8.1 (p = 0.0494) (p = 0.0072) CGI-I, (number of patients,
% in parentheses) Very much improved 3 (1.3) 6 (2.6) 11 (4.5) Much
improved 27 (11.3) 43 (18.3) 53 (21.5) Minimally improved 70 (29.2)
85 (36.2) 80 (32.5) No change 121 (50.4) 85 (36.2) 84 (34.1)
Minimally worse 19 (7.9) 12 (5.1) 16 (6.5) Much worse 0 (0.0) 3
(1.3) 2 (0.8) Very much worse 0 (0.0) 1 (0.4) 0 (0.0) Data
presented as mean .+-. standard deviation or number of patients
(%). UPDRS = Unified Parkinson's Disease Rating Scale; CGI-I =
Clinical Global Impressions-Improvement of illness
TABLE-US-00003 TABLE 3 Correlation between efficacy and patient
demographic factors by multivariate logistic regression analysis ON
time without UPDRS Part II OFF time p for troublesome dyskinesia p
for score (OFF) p for 20 40 hetero- 20 40 hetero- 20 40 hetero-
Characteristic mg/day mg/day geneity mg/day mg/day geneity mg/day
mg/day geneity Age, (y) <65 1.00 (ref) n.s. 1.00 (ref) 1.00
(ref) <0.10 1.00 (ref) n.s. .gtoreq.65 2.65 1.47 2.88 0. 90
[1.65-4.28] [0.76-2.85] [1.41- 5.89] [0.56-1.46] Mean daily OFF
time, (h) <4 1.00 1.00 <0.10 1.00 (ref) 1.00 (ref) <0.10
1.00 (ref) n.s. (ref) (ref) 4 to <8 1.27 1.58 1.09 0.58 1.00
[0.53-3.05] [0.66-3.77] [0.47-2.56] [0.25-1.34] [0.55-1.83]
.gtoreq.8 1.57 6.68 1.19 2.38 0.98 [0.63-3.92] [2.41-18.5]
[0.49-2.91] [0.91-6.21] [0.51-1.89] UPDRS Part III score <20
1.00 (ref) n.s. 1.00 (ref) n.s. 1.00 (ref) n.s. .gtoreq.20 0.88
0.97 0.79 [0.56-1.36] [0.63-1.50] [0.50-1.25] m Hoehn & Yahr
scale at OFF state <3 1.00 (ref) n.s. 1.00 (ref) n.s. 1.00 1.00
<0.10 (ref) (ref) .gtoreq.3 0.63 0.60 0.99 3.50 [0.35-1.15]
[0.33-1.08] [0.41-2.39] [1.36-9.00] UPDRS Part III score CGI-I
Characteristic 20 mg/day 40 mg/day p for heterogeneity 20 mg/day 40
mg/day p for heterogeneity Age, (y) <65 1.00 (ref) n.s. 1.00
(ref) n.s. .gtoreq.65 0.65 1.17 [0.40-1.06] [0.74-1.85] Mean daily
OFF time, (h) <4 1.00 (ref) n.s. 1.00 (ref) n.s. 4 to <8 0.85
1.09 [0.47-1.55] [0.61-1.94] .gtoreq.8 0.53 0.85 [0.27-1.03]
[0.45-1.60] UPDRS Part III score <20 1.00 (ref) n.s. 1.00 (ref)
n.s. .gtoreq.20 2.79 1.49 [1.75-4.46] [0.97-2.30] m Hoehn &
Yahr scale at OFF state <3 1.00 (ref) n.s. 1.00 (ref) n.s.
.gtoreq.3 1.81 1.89 [0.95-3.46] [1.07-3.36] Data are presented as
odds ratio and 95% confident intervals, which were obtained by
multivariate logistic regression analyses controlling for baseline
factors (age, mean daily OFF time, UPDRS Part III score, m Hoehn
& Yahr scale at ON state, and m Hoehn & Yahr scale at OFF
state at baseline). Type III p-values were calculated from
multivariate logistic regression analyses controlling for
interaction between the same baseline factor and istradefylline
dose (20 mg/day or 40 mg/day). UPDRS = Unified Parkinson's Disease
Rating Scale; CGI-I, Clinical Global Impressions-Improvement of
illness; n.s. = not significant; PD = Parkinson's disease; ref =
reference
[0169] While the present invention has been described in detail
with reference to specific embodiments, it is apparent to those
skilled in the art that various changes and modifications can be
made without departing from the spirit and scope of the present
invention. The present application is based on U.S. Provisional
Application (U.S. 62/821,961) filed on Mar. 21, 2019, the entire
contents of which are incorporated herein by reference.
* * * * *